3BL9

Synthetic Gene Encoded DcpS bound to inhibitor DG157493

Summary for 3BL9

• Entry DOI: 10.2210/pdb3bl9/pdb
• Related: 1ST0 1ST4 3BL7 3BLA
• Descriptor: Scavenger mRNA-decapping enzyme DcpS, 5-{[1-(2,3-dichlorobenzyl)piperidin-4-yl]methoxy}quinazoline-2,4-diamine (3 entities in total)
• Functional Keywords: mrna decapping enzyme, dcps, ligand complex, cytoplasm, hydrolase, nonsense-mediated mrna decay, nucleus, polymorphism, structural genomics, psi-2, protein structure initiative, accelerated technologies center for gene to 3d structure, atcg3d
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q96C86
• Total number of polymer chains: 2
• Total formula weight: 70215.57

Authors

Staker, B.L.,Christensen, J.,Stewart, L.,Accelerated Technologies Center for Gene to 3D Structure (ATCG3D) (deposition date: 2007-12-10, release date: 2008-10-21, Last modification date: 2023-08-30)

Primary citation

Singh, J.,Salcius, M.,Liu, S.W.,Staker, B.L.,Mishra, R.,Thurmond, J.,Michaud, G.,Mattoon, D.R.,Printen, J.,Christensen, J.,Bjornsson, J.M.,Pollok, B.A.,Kiledjian, M.,Stewart, L.,Jarecki, J.,Gurney, M.E.
DcpS as a therapeutic target for spinal muscular atrophy.
Acs Chem.Biol., 3:711-722, 2008

PubMed Abstract: Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene, which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene,SMN2, which produces an mRNA that is incorrectly spliced with deletion of the last exon. We described previously the discovery of potent C5-substituted quinazolines that increase SMN2 gene expression by 2-fold. Discovery of potent SMN2 promoter inducers relied on a cellular assay without knowledge of the molecular target. Using protein microarray scanning with a radiolabeled C5-substituted quinazoline probe, we identified the scavenger decapping enzyme, DcpS, as a potential binder. We show that the C5-substituted quinazolines potently inhibit DcpS decapping activity and that the potency of inhibition correlates with potency forSMN2 promoter induction. Binding of C5-substituted quinazolines to DcpS holds the enzyme in an open, catalytically incompetent conformation. DcpS is a nuclear shuttling protein that binds and hydrolyzes the m(7)GpppN mRNA cap structure and a modulator of RNA metabolism. Therefore DcpS represents a novel therapeutic target for modulating gene expression by a small molecule.

PubMed: 18839960
DOI: 10.1021/cb800120t

Experimental method

X-RAY DIFFRACTION (1.8 Å)